The long-term goal of this proposal is to provide a better understanding of the mechanisms of Candida albicans pathogenesis. C. albicans is the most common human fungal pathogen and causes a range of infections including severe systemic disease in immunocompromised individuals. A better understanding of the mechanisms of fungal pathogenesis is therefore needed as new medical strategies are increasing the pool of susceptible immunocompromised patients and current drugs are not very effective for treating systemic infections. A major underlying factor for C. albicans virulence is the ability to switch between budding and hyphal states that differ in their ability to produce virulence factors, grow invasively, disseminate in the bloodstream, and evade the immune system. The studies in this proposal will focus on the plasma membrane since it is the zone of active morphogenesis and is also an important target of antifungal drugs. In particular, the Specific Aims will be to determine the role of two plasma membrane compartments that were discovered in our last grant period. Aim 1 is to identify the factors that form a boundary domain at the neck of emerging hyphae (germ tubes) and determine its role in morphogenesis. Aim 2 is to determine the role of an ergosterol-rich domain that forms in the plasma membrane at the leading edge of hyphal growth. In addition, Aim 3 will examine how remodeling of the plasma membrane by endocytosis contributes to the organization of these special domains and to the presentation of virulence factors. These studies are expected to aid in development of novel therapeutic approaches by providing new insight into the mechanisms underlying C. albicans pathogenesis and also by providing a better understanding of the mechanisms of current antifungal drugs that target the plasma membrane (e.g. amphotericin, fluconazole).